1. Field of the Invention
The invention relates to antagonists of luteinizing hormone-releasing hormone (LH-RH) having improved solubility properties, processes for the preparation of these compounds, medicaments in which these compounds are contained, and therapeutic methods comprising administering the medicaments for the treatment of hormone-dependent tumors such as prostate cancer and ovarian cancer, and hormone-influenced non-malignant disorders such as benign prostate hyperplasia (BPH) and endometriosis.
2. Background Information
LH-RH, also referred to as gonadotropin-releasing hormone (GnRH), stimulates the pituitary secretion of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which control the hormonal and reproductive functions of the gonads. LH-RH antagonists such as the peptide compounds of the present invention selectively block the secretion of LH and FSH by the pituitary gland, and are therapeutically useful in clinical situations in which the suppression of sexual steroids (testicular androgens and ovarian estrogens) is desired; for example, in the treatment of hormone-dependent tumors such as prostate cancer, breast cancer, ovarian cancer, and endometrial cancer, and in the treatment of hormone-influenced non-malignant disorders that are treatable by LH-RH suppression, such as BPH, endometriosis, and uterine fibroids and other leiomyomas. LH-RH receptors are also present on the surfaces of cancerous cells of hormone-dependent tumors (e.g., ovarian cancer) and appear to be involved in signaling pathways that promote proliferation of the cancer cells. Peptide LH-RH antagonists block the activity of these LH-RH receptors and inhibit cancer cell proliferation. Peptide LH-RH antagonists have been shown to be therapeutically effective in clinical use, and to have acceptable pharmacokinetic, safety and commercial profiles.
The nomenclature used for the definition of the peptides disclosed herein agrees with that nomenclature explained by the IUPAC-IUB Commission on Biochemical Nomenclature (European J. Biochem. 1984, 138, 9-37), in which, in agreement with the conventional representation, the amino groups at the N terminus appear to the left and the carboxyl group at the C terminus appears to the right. The LH-RH antagonists such as the peptides according to the invention include naturally occurring and synthetic amino acids, the former including Ala, Val, Leu, Ile, Ser, Thr, Lys, Arg, Asp, Asn, Glu, Gln, Cys, Met, Phe, Tyr, Pro, Trp and His. The abbreviations for the individual amino acid residues are based on the trivial names of the amino acids and are Ala=alanine, Arg=arginine, Gly=glycine, Leu=leucine, Lys=lysine, Pal (3)=3-(3-pyridyl) alanine, Nal(2)=3-(2-naphthyl)-alanine, Phe=phenylalanine, Cpa=4-chlorophenylalanine, Pro=proline, Ser=serine, Thr=threonine, Trp=tryptophan, Try=tyrosine and Sar=sarcosine. All amino acids described here originate from the L series, if not mentioned otherwise. For example, D-Nal(2) is the abbreviation for 3-(2-naphthyl)-D-alanine and Ser is the abbreviation for L-serine. Substitutions on the ε amino group in the side chain of lysine are represented by a term placed in brackets behind Lys, if appropriate in the form of an abbreviation.
Other abbreviations used are:
AcAcetylAtz3-Amino-1,2,4-triazole-5-carbonylB4-(4-Amidinophenyl)amino-1,4-dioxobutylBoctert-ButyloxycarbonylBopBenzotriazol-1-oxy-tris (dimethylamino)-phosphonium hexafluorophosphateDCCDicyclohexylcarbodiimideDCMDichloromethaneDdzDimethoxyphenyl-dimethylmethylenoxy-carbonyl(Dimethoxy-dimethyl-Z)DICDiisopropylcarbodiimideDIPEAN,N-DiisopropylethylamineDMFDimethylformamideFmocFluorenylmethyloxycarbonylHciHomocitrullineHFHydrofluoric acidHOBt1-HydroxybenzotriazoleHPLCHigh-pressure liquid chromatographyMeMethylTFATrifluoroacetic acidZBenzyloxycarbonyl
The peptides according to the invention are analogues of the luteinizing-hormone-releasing hormone (LH-RH), which has the following structure:p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2, (SEQ ID NO: 1)[LH-RH, gonadorelin].
For more than 20 years, researchers have sought selective potent antagonists of the LH-RH decapeptide [M. Karten and J. E. Rivier, Endocrine Reviews 7, 44-66 (1986)] The high interest in such antagonists is based on their usefulness in the field of endocrinology, gynaecology, contraception and cancer. A large number of compounds have been prepared as potential LH-RH antagonists. The most interesting compounds which have been found to date are those compounds whose structures are a modification of the LH-RH structure.
The first series of potent antagonists was obtained by the introduction of aromatic amino acid residues into the positions 1, 2, 3 and 6 or 2, 3 and 6. The customary way of writing the compounds is as follows: the amino acids are first indicated which have taken the place of the amino acids originally present in the peptide chain of LH-RH, the positions in which the exchange took place being marked by superscripted figures. Furthermore, by the notation “LH-RH” placed afterwards it is expressed that these are LH-RH analogues in which the exchange has taken place.
Known antagonists are:
[Ac-D-Cpa1,2, D-Trp3,6] LH-RH (D. H. Coy et al., In: Gross, E. and Meienhofer, J. (Eds) Peptides; Proceedings of the 6th American Peptide Symposium, pp. 775-779, Pierce Chem. Co., Rockville III. (1979): [Ac-Pro1, D-Cpa2, D-Nal(2)3,6] LH-RH (U.S. Pat. No. 4,419,347) and [Ac-Pro1, D-Cpa2, D-Trp3,6] LH-RH (J. L. Pineda, et al., J. Clin. Endocrinol. Metab. 56, 420, 1983).
In order to improve the action of antagonists, basic amino acids, for example D-Arg, were later introduced into the 6 position. For example [Ac-D-Cpa1,2, D-Trp3, D-Arg6, D-Ala10] LH-RH (ORG-30276) (D. H. Coy, et al., Endocrinology 100, 1445, 1982); and [Ac-D-Nal(2)1, D-Phe(4-F)2, D-Trp3, D-Arg6] LH-RH (ORF 18260) (J. E. Rivier et al., in: Vickery B. H. Nestor, Jr. J. J., Hafez, E. S. E (Eds). LHRH and its Analogs, pp. 11-22 MTP Press, Lancaster, UK 1984).
Further potent LH-RH antagonists are described in WO 92/19651, WO 94/19370, WO 92/17025, WO 94/14841, WO 94/13313, EP 0 413 209 A1 and DE 195 44 212 A1, and U.S. Pat. Nos. 5,300,492, and 5,140,009. Peptide LH-RH antagonists are also described in U.S. Pat. Nos. 4,268,044, 4,581,169, 5,527,777, 5,198,533, and 5,942,493, and in WO 97/19953, WO 98/25642, WO 00/55190, EP 0 328 090 A2, and EP 0 413 209 A1.
The latter discloses compounds having a modified ornithine or lysine unit in position 6 and which correspond to the following formula:Ac-D-Nal(2)1-D-Cpa2-D-Pal(3)3-Ser4-Tyr5-D-Xxx6-Leu7-Arg-Pro9-D-Ala10-NH2,
in which D-Xxx is an amino acid group of the general formula VI

Further known LH-RH antagonists are antarelix, ganirelix and cetrorelix.
Antarelix:Ac-D-Nal(2)1-D-Cpa2-D-Pal(3)3-Ser4-Tyr5−D-Hci6-Leu7-Lys(iPr)8-Pro9-D-Ala10-NH2 Ganirelix:Ac-D-Nal(2)1-D-Cpa2-D-Pal(3)3-Ser4-Tyr5-D-hArg(Et)26-Leu7-hArg(Et)28-Pro9-D-Ala10-NH2 Cetrorelix:Ac-D-Nal(2)1-D-Cpa2-D-Pal(3)3-Ser4-Tyr5-D-Cit6-Leu7-Arg8-Pro9-D-Ala10-NH2.